Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore

10.1186/1471-2407-13-389BMC Cancer13-BCMA

No association between polymorphisms in the BDNF gene and age at onset in Huntington disease

BACKGROUND: Recent evidence suggests that brain-derived neurotrophic factor (BDNF) is an attractive candidate for modifying age at onset (AO) in Huntington disease (HD). In particular, the functional Val66Met polymorphism appeared to exert a significant effect. Here we evaluate BDNF variability with respect to AO of HD using markers that represent the entire locus. METHODS: Five selected tagging polymorphisms were genotyped across a 65 kb region comprising the BDNF gene in a well established cohort of 250 unrelated German HD patients. RESULTS: Addition of BDNF genotype variations or one of the marker haplotypes to the effect of CAG repeat lengths did not affect the variance of the AO. CONCLUSION: We were unable to verify a recently reported association between the functional Val66Met polymorphism in the BDNF gene and AO in HD. From our findings, we conclude that neither sequence variations in nor near the gene contribute significantly to the variance of AO

Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 mu g/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 mu g/l, P = 0.0004; itself higher than the normal level (3.4 mu g/l, range from 0.5 to 17.2 mu g/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level >= 7 mu g/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels >= 7 mu g/l is 46%. Therefore, selection of patients with an AFP level above 7 mu g/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy

Technologies for the global energy transition

The availability of reliable, affordable and mature technologies is at the basis of an effective decarbonization strategy, that should be in turn supported by timely and accurate policies. Due to the large differences across sectors and countries, there is no silver bullet to support decarbonization, but a combination of multiple technologies will be required to reach the challenging goal of decarbonizing the energy sector. This chapter presents a focus on the current technological solutions that are available in four main sectors: power generation, industry, transport and buildings. The aim of this work is to highlight the main strengths and weaknesses of the current technologies, to help the reader in understanding which are the main opportunities and challenges related to the development and deployment of each of them, as well as their potential contribution to the decarbonization targets. The chapter also provides strategies and policy recommendations from a technology point of view on how to decarbonize the global energy systems by mid-century and of the necessity to take a systems approach

Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene

Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1.peer-reviewe

Autosomal dominant hereditary spastic paraplegia: Novel mutations in the REEP1 gene (SPG31)

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>SPG4 </it>gene (spastin) and in the <it>SPG3A </it>gene (atlastin) account for the majority of 'pure' autosomal dominant form of hereditary spastic paraplegia (HSP). Recently, mutations in the <it>REEP1 </it>gene were identified to cause autosomal dominant HSP type SPG31. The purpose of this study was to determine the prevalence of <it>REEP1 </it>mutations in a cohort of 162 unrelated Caucasian index patients with 'pure' HSP and a positive family history (at least two persons per family presented symptoms).</p> <p>Methods</p> <p>162 patients were screened for mutations by, both, DHPLC and direct sequencing.</p> <p>Results</p> <p>Ten mutations were identified in the <it>REEP1 </it>gene, these included eight novel mutations comprising small insertions/deletions causing frame shifts and subsequently premature stop codons, one nonsense mutation and one splice site mutation as well as two missense mutations. Both missense mutations and the splice site mutation were not identified in 170 control subjects.</p> <p>Conclusion</p> <p>In our HSP cohort we found pathogenic mutations in 4.3% of cases with autosomal dominant inheritance. Our results confirm the previously observed mutation range of 3% to 6.5%, respectively, and they widen the spectrum of <it>REEP1 </it>mutations.</p